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WO1996004273A1 - Nouveaux derives de pyrazole utilises comme antagonistes de l'angiotensine ii - Google Patents

Nouveaux derives de pyrazole utilises comme antagonistes de l'angiotensine ii Download PDF

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Publication number
WO1996004273A1
WO1996004273A1 PCT/EP1995/003086 EP9503086W WO9604273A1 WO 1996004273 A1 WO1996004273 A1 WO 1996004273A1 EP 9503086 W EP9503086 W EP 9503086W WO 9604273 A1 WO9604273 A1 WO 9604273A1
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Prior art keywords
methyl
compound
alkyl
pyrazole
biphenyl
Prior art date
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PCT/EP1995/003086
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English (en)
Inventor
Carmen Almansa
Concepción GONZALES
Maria Carmen Torres
Elena Carceller
Javier Bartroli
Original Assignee
J. Uriach & Cia, S.A.
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Application filed by J. Uriach & Cia, S.A. filed Critical J. Uriach & Cia, S.A.
Priority to AU32563/95A priority Critical patent/AU3256395A/en
Priority to US08/624,459 priority patent/US5827863A/en
Priority to JP8506213A priority patent/JPH09504804A/ja
Priority to EP95929067A priority patent/EP0721454A1/fr
Publication of WO1996004273A1 publication Critical patent/WO1996004273A1/fr
Priority to NO961333A priority patent/NO961333L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new pyrazole derivatives which are potent angiotensin II antagonists.
  • the invention also relates to a process for their preparation, to the pharmaceutical compositions containing them and to their use for the manufacture of medicaments for the treatment or prevention of hypertension, congestive heart failure, elevated intraocular pressure and other diseases or medical conditions in which the action of angiotensin II is implicated.
  • the renin-angiotensin system plays a key role in the regulation of blood pressure and volume homeostasis. Activation of the renin-angiotensin cascade begins with renin secretion from the juxtaglomerular apparatus of the kidney and culminates in the formation of the octapeptide angiotensin II.
  • Angiotensin II exerts its biological effects via interactions with specific receptors present in many tissues.
  • Two basic types of angiotensin II receptors have been characterized so far, both with a broad distribution: the AT 1 receptors, responsible for the majority of effects attributed to this peptide, and the AT 2 receptors, the functional role of which has not yet been identified.
  • angiotensin II The main effects of angiotensin II are the regulation of blood pressure through vasoconstriction thereby effecting an increase in vascular resistances, the regulation of volemia through the stimulation of the release of vasopressin and particularly aldosterone, which induces saline retention, and the regulation of the adrenocorticotropic hormone (ACTH).
  • Angiotensin II can act as a neuropeptide at the central nervous system and can play a modulating function in the release of other neurotransmiters.
  • angiotensin II is involved in several cerebral processes related with the learning function, memory and the like.
  • angiotensin II One of the possible modes of interfering with the RAS is to block the action of angiotensin II at the receptor level. Although several peptidic analogues of angiotensin II having greater affinity for its receptors than angiotensin II itself have been discovered, their therapeutic use has been severely limited by their lack of bioavailability and short duration of action.
  • Patent applications EP 253310 and WO 91/05025 disclose compounds related to those described in the present invention.
  • the present invention relates to novel pyrazoles of general formula I:
  • R 1 represents hydrogen, C 1 -6 alkyl, C 1 -6 haloalkyl, C 3-7 cycloalkyl, aryl, or -(CH 2 ) m COR 5 ;
  • R 2 represen ts hydrogen, halogen, C 1 -6 alkyl, C 1 -6 haloalkyl, C 3- 7 cycloalkyl, C 3-7 cycloalkylC 1 -4 alkyl, C 1 -6 hydroxyalkyl, C 1 -6 alkoxy C 1 -4 alkyl, aryl or aryl C 1 -4 alkyl;
  • R 3 represents hydrogen, -(Cr 2 ) n R 6 or -(CH 2 ) p COR 7 ;
  • either a, b, c and d represent CR or one of a, b, c and d represents N and the remaining groups represent CR, wherein each R independently represents hydrogen, halogen, C 1 -4 alkyl, hydroxy, C 1 -4 alkoxy, nitro, amino, C 1 -4 alkylamino or C 1 -4 dialkylamino;
  • R 4 represents -CO 2 R 8 ; -tetrazol-5-yl; tetrazol-5-ylmethyl; -CONH (tetrazol- 5-yl); -CONHSO 2 R 9 ; -CONHSO 2 -Het; -CONHOR 8 ; -CONH 2 ; -CONR 8 R 9 -COCH 2 COR 8 ; -COCH 2 CO 2 R 8 ; -CONHNHSO 2 R 9 ; -CONHNHCONH 2 -CH 2 NHSO 2 R 9 ; -CH 2 CO 2 R 8 ; -CH 2 SO 2 N HC OR 8 ; -CH 2 SO 2 N HCONHR 8 -CH 2 CONHSO 2 R 9 ; -CH 2 SO 2 NH-Het; -CH 2 NHCOR 8 ; -NHSO 2 R 9 ; -NHCOR 8 -NHCONHSO 2 R 9 ; -NHSO 2 NHCOR 8 ; -SO 3 H; -
  • R 5 represents hydrogen, hydroxy, C 1 -6 alkyl, C 1 -6 alkoxy, aryl, aryloxy or a group -NR 10 R 11 ;
  • R 6 represents hydroxy, C 1 -6 alkoxy, aryloxy, arylC 1 -4 alkoxy or C 1 -6 alkylcarbonyloxy;
  • R 7 represents hydrogen, hydroxy, C 1 -6 alkyl, C 1 -6 alkoxy, aryl, aryloxy, arylC 1 -4 alkoxy, carboxy, C 1 -4 alkoxycarbonyl, a group -OR 12 or a group -NR 10 R 11 ;
  • R 10 and R 1 1 independently represent hydrogen or C 1 -6 alkyl
  • R 1 2 represents C 1 -6 alkylcarbonyloxy C 1 -4 alkyl, C3-7 cycloalkyl- carbonyloxy C 1 -4 alkyl, C 1 -6 alkoxycarbonyloxy C 1 -4 alkyl, C 3-7 cycloalkyloxy- carbonyloxy C 1 -4 alkyl, C 1 -6 alkoxycarbonyl C 1 -4 alkyl, C 3-7 cycloalkyloxycarbonyl- C 1-4 alkyl, C 1 -6 alkylcarbonylamino C 1 -4 alkyl, C 3-7 cycloalkylcarbonylamino C 1 -4 alkyl, a group of formula -(CH 2 ) q R 13 , or a group of formula -(CH 2 ) r OR 13 ;
  • R 13 represents phenyl optionally substituted with a group arylcarbonyl, C 1-6 alkylcarbonyl or aryloxy;
  • n, q and r independently represent 1, 2 or 3;
  • p 0, 1 or 2;
  • aryl whenever appearing in the above definitions, represents phenyl or phenyl substituted with 1, 2, 3 or 4 groups selected from C 1 -4 alkyl, C 1 -4 haloalkyl, C 1 -4 alkoxy, C 1 -4 haloalkoxy, halogen, nitro, cyano, hydroxy, amino, C 1 -4 alkylamino or C 1 -4 dialkylamino;
  • the present invention also provides a pharmaceutical composition which comprises an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof in admixture with a pharmaceutically acceptable excipient.
  • the invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment or prevention of diseases or medical conditions in which angiotensin II is involved in a mammal, which may be a human being.
  • a mammal which may be a human being.
  • Preferred is the use for the manufacture of a medicament for the treatment or prevention of hypertension, congestive heart failure and elevated intraocular pressure.
  • the invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof for the treatment or prevention of diseases or medical conditions in which angiotensin II is involved in a mammal, which may be a human being.
  • a mammal which may be a human being.
  • Preferred is the use for the treatment or prevention of hypertension, congestive heart failure and elevated intraocular pressure.
  • the invention further provides a method of treating diseases or medical conditions in which angiotensin II is involved in a mammal, which comprises administering to said mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating or preventing hypertension, congestive heart failure and elevated intraocular pressure in a mammal in need thereof the method comprising administering to the mammal an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof.
  • the invention still further provides a process for preparing a compound of formula I, which comprises:
  • R 4 * represents a group R 4 or a group convertible thereto, and either one of R 14 and R 1 5 represents halogen, methanesulfonyloxy, toluenesulfonyloxy or trifluoromethanesulfonyloxy and the other represents a group -Sn(R 16 ) 3 , -B(OH) 2 or -B(OR 17 ) (OR 18 ) or both of them represent halogen, wherein R 1 6 represents a C 1 -4 alkyl group and R 17 and R 18 represent each C 1 -4 alkyl or R 17 and R 18 together with the oxygen atoms to which they are linked and the boron atom form a 1,3,2-dioxaborane or a 1,3,2-dioxaborolane ring, which may be optionally substituted with C 1 -4 alkyl groups), followed, if necessary
  • R 4 * represents a group R 4 or a group convertible thereto
  • steps A, B, C or D treating a compound of formula I with an acid or a base to give the corresponding salt.
  • C 1 -n alkyl as a group or part of a group, means a linear or branched alkyl chain containing from 1 to n carbon atoms. Therefore, when n is 4 it includes the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • n 6 it includes, among others, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 1 -methylpentyl, 2- methylpentyl, 3-methylpentyl.
  • C 1 -n alkoxy as a group or part of a group, means a group derived from the union of a C 1 -n alkyl group to an oxygen atom of an ether functional group.
  • n 4
  • this term includes the groups methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • n 6
  • a halogen atom means fluorine, chlorine, bromine or iodine.
  • a C 1 -6 haloalkyl group means a group resulting from the substitution of one or more hydrogen atoms of a C 1 -6 alkyl group by one or more halogen atoms (i.e. fluorine, chlorine, bromine or iodine), which can be the same or different.
  • halogen atoms i.e. fluorine, chlorine, bromine or iodine
  • Examples include trifluoromethyl, fluoromethyl, chloroethyl, fluoroethyl, iodoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, fluoropropyl, chloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, fluorobutyl, nonafluorobutyl, fluoropentyl, fluorohexyl.
  • a perfluoro-(C 1 -4 )alkyl group means a group resulting from the substitution of all hydrogen atoms of a C 1 -4 alkyl group by fluorine atoms. Examples include trifluoromethyl, pentafluoroethyl, heptafluoropropyl, and nonafluorobutyl.
  • a C 1 -6 hydroxyalkyl group means a group resulting from the substitution of one hydrogen atom of a C 1 -6 alkyl group by one hydroxyl group. Examples include hydroxymethyl, 2-hydroxyethyl, 1 -hydroxyethyl, 3- hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2- hydroxybutyl, 1-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl.
  • C 3-7 cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • a C 3-7 cycloalkylC 1 -4 alkyl group represents a group resulting from the substitution of one hydrogen atom of a C 1 -4 alkyl group by a C 3-7 cycloalkyl group; examples include among others cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.
  • a C 1 -4 alkylamino or C 1 -4 dialkylamino group represents a group resulting from the substitution of one or two hydrogen atoms, respectively, of an amino group by one or two C 1 -4 alkyl groups, which can be the same or different.
  • Examples include methylamino, dimethylamino, ethylamino, diethylamino, e thyl me thylamino, propylamino, dipropyl amino, isopropylamino and diisopropylamino.
  • a group aryl C 1 -4 alkyl represents a group resulting from the substitution of one hydrogen atom of a C 1 -4 alkyl group by a group aryl, such as for example a group benzyl.
  • a group aryl C 1 -4 alkoxy represents a group resulting from the union of a aryl C 1 -4 alkyl group to an oxygen atom of an ether functional group, such as for example a group benzyloxy.
  • Examples of a group C 1 -6 alkylcarbonyloxy C 1 -4 alkyl include formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryl- oxymethyl, hexanoyloxymethyl, 1 -(formyloxy)ethyl, 1 -(acetoxy)ethyl, 1- (propionyloxy)e thyl, 1 -(bu tyryloxy)ethyl, 1 -(isobu tyryloxy)ethyl, 1 - (pivaloyloxy)ethyl, 1 -( valeryloxy)ethyl, 1 -(isovaleryloxy)e thyl, 1 - (hexanoyloxy)ethyl, 2-(formyloxy)ethyl, 2-(acetoxy)ethyl, 2-(
  • Examples of a group C 3 -7 cycloalkylcarbonyloxy C 1 -4 alkyl include cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbo- nyloxymethyl, cyclohexylcarbonyloxymethyl, cycloheptylcarbonyloxymethyl, 1- (cyclopropylcarbonyloxy)ethyl, 1 -(cyclobutylcarbonyloxy)ethyl, 1-(cyclopentyl- carbonyloxy)ethyl, 1 -(cyclohexylcarbonyloxy)ethyl, 1-(cycloheptylcarbonyloxy)- ethyl, 1-(cyclopropylcarbonyloxy)propyl, 1-(cyclobutylcarbonyloxy)propyl, 1- (cyclopentylcarbonyloxy)propyl, 1 -(cyclohexylcarbonyloxy)propyl
  • Examples of a group C 1 - 6 al koxyca rbony loxy C 1 -4 alkyl include methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, sec-butoxycarbonyloxymethyl, tert-butoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, isopentyloxycarbonyloxymethyl, neopentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)ethyl, 1- (isopropoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)ethyl, 1 -(isobutoxycarbonyloxy)ethyl, 1-(sec-butoxy
  • Examples of a group C 3-7 cycloalkyloxycarbonyloxy C 1 -4 alkyl include cyclopropyloxy carbonyloxymethyl, cyclobutyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cycloheptyloxycarbonyloxymethyl, 1 -(cyclopropyloxycarbonyloxy)ethyl, 1-(cyclobutyloxycarbonyloxy)ethyl, 1 -(cyclopentyloxycarbonyloxy)ethyl, 1 -(cyclohexyloxycarbonyloxy)ethyl, 1-(cycloheptyloxycarbonyloxy)ethyl, 1-(cyclopropyloxycarbonyloxy)propyl, 1 -(cyclobutyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)propyl, 1 -(cyclohexy
  • Examples of a group C 1 -6 alkoxycarbonyl C 1 -4 alkyl include methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl, butoxycarbonylmethyl, isobutoxycarbonylmethyl, sec-butoxycarbonylmethyl, tert-butoxycarbonylmethyl, pentyloxycarbonylmethyl, isopen tyloxycarbonylmethyl, neopentyloxycarbonylmethyl, hexyloxycarbonylmethyl, 1-(methoxycarbonyl)ethyl, 1-(ethoxycarbonyl)ethyl, 1- (propoxycarbonyl)ethyl, 1-(isopropoxycarbonyl)ethyl, 1-(butoxycarbonyl)ethyl, 1- (isobutoxycarbonyl)ethyl, 1 -(sec-butoxycarbonyl)ethyl, 1-(tert-butoxycarbonyl)- eth
  • Examples of a group C 3-7 cycloalkyloxycarbonyl C 1 -4 alkyl include cyclopropyloxycarbonylmethyl, cyclobutyloxycarbonylmethyl, cyclopentyloxycarbonylmethyl, cyclohexyloxycarbonylmethyl, cycloheptyloxycarbonylmethyl, 1-(cyclopropyloxycarbonyl)ethyl, 1-(cyclobutyloxycarbonyl)ethyl, 1-(cyclopentyloxycarbonyl)ethyl, 1-(cyclohexyloxycarbonyl)ethyl, 1-(cycloheptyloxycarbonyl)- ethyl, 1-(cyclopropyloxycarbonyl)propyl, 1 -(cyclobutyloxycarbonyl)propyl, 1- (cyclopentyloxycarbonyl)propyl, 1 -(cyclohexyloxycarbonyl)propyl, 1- (cycloheptyl
  • Examples of a group C 1 -6 alkylcarbonylamino C 1 -4 alkyl include methylcarbonylaminomethyl, ethylcarbonylaminomethyl, propylcarbonylaminomethyl, isopropylcarbonylaminomethyl, butylcarbonylaminomethyl, isobutyl carbonyl am i nome th yl , sec -bu tylca rbon yla minomethyl, tert- butylcarbonylaminomethyl, pentylcarbonylaminomethyl, isopentylcarbonylaminomethyl, neopentylcarbonylaminomethyl, hexylcarbonylaminomethyl, 1- (methylcarbonylamino)ethyl, 1-(ethylcarbonylamino)ethyl, 1-(propylcarbonylamino)ethyl, 1-(isopropylcarbonylamino)ethyl, 1 -(butylcarbony
  • Examples of a group C 3-7 cycloalkylcarbonylamino C 1 -4 alkyl include cyclopropylcarbonylaminomethyl, cyclobutylcarbonylaminomethyl, cyclopentylcarbonylaminomethyl, cyclohexylcarbonylaminomethyl, cycloheptylcarbonylaminomethyl, 1 -(cyclopropylcarbonylamino)ethyl, 1-(cyclobutylcarbonylamino)ethyl, 1 -(cyclopentylcarbonylamino)ethyl, 1 -(cyclohexylcarbonylamino)ethyl, 1 -(cycloheptylcarbonylamino)ethyl, 1 -(cyclopropylcarbonylamino)propyl, 1 -(cyclobutylcarbonylamino)propyl, 1 -(cyclopentylcarbonylamino)propyl, 1 -
  • Examples of the group Het defined above in connection with the substituent R 4 include pyridine, pyrimidine, pyrazine, pyridazine, furan, pyrrole, tiophene, imidazole, triazole, thiazole, oxazole and isoxazole.
  • Preferred compounds of the present invention include those in which, independently or in any compatible combination:
  • R 1 is adjacent to the biphenylmethyl or phenylpyridylmethyl moiety
  • R 1 represents C 1 -6 alkyl
  • R 2 represents hydrogen, C 1 -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1 -4 alkyl, aryl or aryl C 1 -4 alkyl;
  • R 3 represents -COR 7 ;
  • R 4 represents -CO 2 R 8 ; -tetrazol-5-yl; -NHSO 2 R 9 ; -SO 2 N H R 8 ; -SO 2 NHCO 2 R 9 or -SO 2 NHCOR 8 .
  • a preferred class of compounds of formula I is that wherein R 1 is adjacent to the biphenylmethyl or phenylpyridylmethyl moiety, thus providing compounds represented by formula la:
  • a more preferred class of compounds of formula I is that of formula la wherein:
  • R 1 represents C 1 -6 alkyl
  • a further preferred class of compounds of formula I is that of formula la wherein:
  • R 1 represents C 1 -6 alkyl
  • a, b, c and d are each CR;
  • R, R 2 , R 3 and R 4 have the previously defined meaning.
  • a yet more preferred class of compounds of formula I is that of formula la wherein:
  • R 1 represents C 2-4 alkyl
  • a, b, c and d are each CR;
  • R 2 represents hydrogen, C 1 -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1 -4 alkyl, aryl or aryl C 1 -4 alkyl;
  • R, R 3 and R 4 have the previously defined meaning.
  • R 1 represents C 2-4 alkyl; a, b, c and d are each CR;
  • R 2 represents hydrogen, C 1 -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1 -4 alkyl, aryl or aryl C 1 -4 alkyl;
  • R 3 represents -COR 7 ;
  • R, R 4 and R 7 have the previously defined meaning.
  • a particularly preferred class of compounds of formula I is that of formula la wherein:
  • R 1 represents C 2-4 alkyl
  • a, b, c and d are each CR;
  • R 2 represents hydrogen, C 1 -6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1 -4 alkyl, aryl or aryl C 1 -4 alkyl;
  • R 3 represents -COR 7 ;
  • R 4 represents -CO 2 R 8 ; -te trazol-5-yl; -N HSO 2 R 9 ; -SO 2 N H R 8 ; -SO 2 NHCO 2 R 9 or -SO 2 NHCOR 8 ; and
  • R, R 7 , R 8 and R 9 have the previously defined meaning.
  • the compounds of the present invention contain one or more basic nitrogen atoms and can contain one or more acid hydrogen atoms and, consequently, they can form salts with acids and bases both organic and inorganic, which salts are also included in the present invention.
  • these salts There is no limitation on the nature of these salts, provided that, when used for therapeutic purposes, they are pharmaceutically acceptable, which, as is well known in the art, means that they do not have reduced activity (or unacceptable reduced activity) or increased toxicity (or unacceptable increased toxicity) compared with the free compounds.
  • salts with inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc; and salts formed with pharmaceutically acceptable amines such as ammonia, alkylamines, hydroxyalkylamines, lysine, arginine, N-methylglucamine, procaine and the like; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, perchloric acid, sulfuric acid, or phosphoric acid; and salts with organic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid or maleic acid.
  • inorganic cations such as sodium, potassium, calcium, magnesium, lithium, aluminium, zinc, etc
  • salts formed with pharmaceutically acceptable amines such as ammoni
  • the salts are prepared by treatment of the compound of formula I with a sufficient amount of the desired acid or base to produce the salt in a conventional manner.
  • Free bases and their salts differ in certain physical properties, such as solubility, but they are equivalent for the purposes of the invention.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for the purposes of the invention.
  • Some compounds of the present invention can exist as different diastereoisomers and/or optical isomers.
  • Diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization.
  • the optical isomers can be resolved using any of the conventional techniques of optical resolution to give optically pure isomers. Such a resolution can be performed in any chiral synthetic intermediate as well as in the products of general formula I .
  • the optical resolution techniques include separation by chromatography on a chiral phase or formation of a diastereoisomeric pair, resolution and subsequent recovery of the two enantiomers.
  • the optically pure isomers can also be individually obtained using enantiospecific synthesis.
  • the present invention covers both the individual isomers and their mixtures (e.g. racemic mixtures), whether as obtained by synthesis or by physically mixing them up.
  • the compounds of formula I may be prepared using the methods described below. It will be apparent to those skilled in the art that the precise method used for the preparation of a given compound may vary depending on its chemical structure. Moreover, in some of the processes described below it will be desirable or necessary to protect reactive or labile groups using conventional protecting groups, for example the groups described below. Both the nature of these protecting groups and the procedures for their introduction and removal are well known in the art.
  • the compounds of general formula I may be obtained by reaction of a compound of general formula II with a compound of general formula III
  • R 4 * represents a group R 4 or a group convertible to R 4
  • one of R 14 and R 1 5 represents a halogen a tom, for example bromine or iodine, or a methanesulfonyloxy, toluenesulfonyloxy or trifluoromethanesulfonyloxy group
  • the other represents -Sn(R 16 ) 3 , -B(OH) 2 or -B(OR 17 )(OR 18 ), wherein R 16 represents a C 1 -4 alkyl group and R 1 7 and R 18 represent each C 1 -4 alkyl or R 17 and R 18 together with the oxygen atoms to which they are linked and the boron atom form a 1,3,2-dioxaborane or a 1,3,2-dioxaborolane ring, which may be optionally substituted with C 1 -4
  • This reaction can be carried out in the presence of a transition metal catalyst such as tetrakis(triphenylphosphine)palladium (0), palladium acetate and triphenylphosphine or palladium on carbon and triphenylphosphine, and preferably in the presence of a base such as an alkali or alkaline earth metal carbonate, for example sodium carbonate, or in the presence of a fluoride salt, for example cesium fluoride.
  • a transition metal catalyst such as tetrakis(triphenylphosphine)palladium (0), palladium acetate and triphenylphosphine or palladium on carbon and triphenylphosphine
  • a base such as an alkali or alkaline earth metal carbonate, for example sodium carbonate
  • a fluoride salt for example cesium fluoride.
  • the reaction is performed in a suitable solvent such as an aromatic hydrocarbon (for example toluene or benzene), an ether (for example dimethoxyethane, diethoxymethane or tetrahydrofuran), water or mixtures thereof, at a suitable temperature, preferably between room temperature and that of the boiling point of the solvent, and during a reaction time preferably between 5 and 48 h.
  • a suitable solvent such as an aromatic hydrocarbon (for example toluene or benzene), an ether (for example dimethoxyethane, diethoxymethane or tetrahydrofuran), water or mixtures thereof.
  • this coupling may be carried out as a one-pot reaction by generating the boronic acid derivative in situ, which avoids the need to isolate it.
  • Examples of this kind of coupling have been described in Maddaford S. P., Keay B. A., J. Org. Chem., 1994, 59, 6501.
  • the compounds of formula I may be obtained by a nickel- catalyzed cross-coupling reaction of a compound of formula II with a compound of formula III, wherein R 14 and R 1 5 represent each a halogen atom.
  • This reaction can be carried out in the reported conditions, for example by treatment with a catalytic amount of NiCl 2 and triphenylphosphine in the presence of zinc in a suitable solvent such as pyridine.
  • a compound of formula I may also be obtained by reaction of a compound of formula IV
  • R 4 * represents a group R 4 or a group convertible thereto
  • a suitable solvent preferably a polar solvent such as an alcohol (e.g. ethanol), an ether (e.g. tetrahydrofuran or dioxan) or acetic acid, at a temperature preferably between room temperature and that of the boiling point of the solvent and during a reaction time preferably between 2 and 24 h.
  • a suitable solvent preferably a polar solvent such as an alcohol (e.g. ethanol), an ether (e.g. tetrahydrofuran or dioxan) or acetic acid
  • protecting groups it is possible to use any of the conventional protecting groups which are widely described in the literature, for example those described in Greene T.W., "Protective Groups in Organic Synthesis", John Wiley & Sons, New York, 1981.
  • carboxy protecting groups it is possible to use C 1 -4 alkyl esters, such as methyl or tert-butyl, or aryl-C 1 -4 alkyl esters, such as benzyl.
  • hydroxy protecting groups it is possible to employ silylic ethers, such as tert- butyldimethylsilyl, or aryl C 1 -4 alkyl ethers, such as benzyl.
  • the tetrazolyl group can be protected with, for example, a triphenylmethyl group (i.e. a trityl group), a tert-butyl group or a benzyl group.
  • alkyl esters may be cleaved by hydrolysis in the presence of a base such as an alkali metal hydroxide, for example potassium hydroxide or sodium hydroxide, in a suitable solvent such as an alcohol, for example ethanol, or alcohol-water mixtures, at a temperature between room temperature and that of the boiling point of the solvent and during a period of time preferably between 2 and 24 h;
  • aryl C 1 -4 alkyl groups may be cleaved by hydrogenolysis in the presence of a noble metal catalyst such as palladium on charcoal in a suitable solvent such as an alcohol, for example ethanol, at a temperature between room temperature and that of the boiling point of the solvent, at a pressure between atmospheric pressure and 10 atmospheres and a reaction time preferably between 1 and 48 h;
  • a triphenylmethyltetrazole group can be converted into a tetrazole group by treatment with an acid such as hydrochloric acid or formic acid in
  • R 4 * has been defined as a group R 4 or a group convertible thereto.
  • the conversion of a group R 4 * into a group R 4 is carried out in one or a plurality of steps using standard methodology and can be effected at any stage of the synthesis or in the final step.
  • Examples of these conversions include: the conversion of a nitrile group into a tetrazole group by treatment with a suitable azide such as sodium azide, ammonium azide (which may be prepared in situ from sodium azide and ammonium chloride) in a suitable solvent such as a polar solvent, for example dimethylformamide or N-methylpyrrolidone a t a suitable temperature, preferably between room temperature and that of the boiling point of the solvent, and during a reaction time between 1 and 96 h, or a trialkyltin azide, for example tributyltin azide (previously prepared or prepared in situ from sodium azide and tributyltin chloride) in an apolar solvent such as an aromatic hydrocarbon, for example xylene or toluene, at a suitable temperature, preferably between room temperature and that of the boiling point of the solvent, and during a reaction time between 1 and 96 h; the hydrolysis of an ester group to give a carboxy group, in
  • a compound of formula I may also be obtained by interconversion of another compound of formula I in one or a plurality of steps.
  • a compound of formula I wherein R 1 represents hydrogen can be converted into a compound of formula I wherein R 1 represents C 1 -6 alkyl or -(CH 2 ) m COR 5 by alkylation with the corresponding alkylating agent, such as for example an alkyl halide, preferably an alkyl iodide.
  • the reaction is carried out by heating a compound of formula I and the alkylating agent at a temperature between 60 °C and that of the boiling point of the alkylating agent, or in the presence of a base such as a metal hydride (e.g.
  • a suitable solvent preferably a polar solvent such as a substituted amide, for example dimethylformamide, an ether, for example tetrahydrofuran or dimethoxyethane, or acetone at a temperature preferably between -20 °C and that of the boiling point of the solvent.
  • a suitable solvent preferably a polar solvent such as a substituted amide, for example dimethylformamide, an ether, for example tetrahydrofuran or dimethoxyethane, or acetone at a temperature preferably between -20 °C and that of the boiling point of the solvent.
  • interconversion between compounds of formula I is the halogenation of a compound of formula I wherein R 2 represents hydrogen to give a compound of formula I wherein R 2 represents halogen.
  • This transformation may be effected by treatment with a halogenating agent such as X 2 (wherein X represents a halogen atom) in a suitable solvent such as water or chloroform or with N-bromosuccinimide or N-chlorosuccinimide in a suitable solvent such as a halogenated hydrocarbon, for example carbon tetrachloride or chloroform, at a suitable temperature, preferably between room temperature and that of the boiling point of the solvent.
  • a halogenating agent such as X 2 (wherein X represents a halogen atom)
  • suitable solvent such as water or chloroform or with N-bromosuccinimide or N-chlorosuccinimide in a suitable solvent such as a halogenated hydrocarbon, for example carbon tetrachloride or
  • a group R 3 in a compound of formula I (or in any synthetic intermediate thereof) into another group R 3 using standard methods of organic synthesis.
  • an ester can be converted into a carboxy group by hydrolysis by the procedures described above.
  • a metal hydride reducing agent such as lithium aluminum hydride or lithium borohydride in a suitable solvent such as ether, tetrahydrofuran or methanol at a temperature preferably between room temperature and that of the boiling point of the solvent to give the corresponding alcohol.
  • a hydroxy group can be oxidized by treatment with a suitable oxidising agent to give an aldehyde.
  • the oxidation of a hydroxy group to an aldehyde can be effected by treatment for example with manganese dioxide ir. a suitable sol vent such as dichloromethane or by treatment with tetra-n-propylammonium perru thenate in the presence of 4- methylmorpholine N-oxide in a suitable solvent such as dichloromethane- acetonitrile mixtures.
  • a hydroxy group can also be converted into a carboxy group by treatment with a stronger oxidising agent such as potassium permanganate or sodium chlori te wi th sodium dihydrogenphosphate.
  • a carboxy group may be converted into a variety of groups using standard procedures.
  • it can be converted into a carboxamide group of formula -CONR 1 0 R 1 1 by reaction with an amine of formula NHR 10 R 1 1 in the presence of a condensing agent such as a carbodiimide (for example dicyclohexylcarbodiimide) or carbonyldiimidazole, or alternatively by treatmen t with 1 -hydroxybenzotriazole and a carbodiimide such as dicyclohexylcarbodiimide to form in situ an activated ester and subsequent reaction of said ester with an amine of formula NHR 1 0 R 1 1 in an inert solvent such as dimethylformamide or dichloromethane.
  • a condensing agent such as a carbodiimide (for example dicyclohexylcarbodiimide) or carbonyldiimidazole, or alternatively by treatmen t with 1 -hydroxybenzotri
  • a carboxy group can be readily converted into an ester group following standard procedures; for example, it can be transformed into an ester group of formula -COOR 1 2 by treatment with a compound of formula R 12 -L (wherein R 12 has the previously described meaning and L represents a leaving group such as a halogen atom) in the presence of a base such as potassium carbonate and preferably in the presence of potassium iodide in a suitable solvent such as dimethylformamide.
  • R 12 has the previously described meaning and L represents a leaving group such as a halogen atom
  • a carboxy group can also be converted to a hydrogen atom by decarboxylation in the presence of an acid such as hydrochloric acid in a suitable solvent such as acetonitrile at a temperature between room temperature and that of the boiling point of the solvent, preferably at the temperature of the boiling point of the solvent.
  • a compound of formula 1 wherein R 3 represents carboxy can also be obtained from a compound of formula I wherein R 3 is hydrogen by treatment with oxalyl chloride followed by hydrolysis at a temperature between room temperature and that of the boiling point of the solvent and during a reaction time between 2 and 24 h.
  • a group R 4 in a compound of formula I can also be used to generate other groups R 4 by methods known to those skilled in the art, thus giving rise to different compounds of formula I.
  • an ester group can easily be converted into a carboxy group by hydrolysis following the procedures described above.
  • a carboxy group may be converted to a carboxamide group following analogous procedures to those described above in connection with the substituent R 3 .
  • a carboxy group may also be converted to a group -CONHSO 2 R 9 , wherein R 9 has the previously described meaning, by treatment with a sulfonamide of formula R 9 S O 2 N H 2 under the usual condi tions known to one skilled i n the art.
  • an alkylaminosulfonyl group may be converted to an amino sulfonyl group by hydrolysis and this may be derivatized using standard procedures by treatment for example with an acid chloride of formula R 8 COCl, a chloroformate derivative of formula R 9 OCOCI or a compound of formula H 2 NCOCI or R 8 R 9 NCOCI.
  • the salts of the compounds of formula I can be prepared by conventional procedures by treatment for example with an acid such as hydrochloric acid, sulfuric acid, nitric acid, oxalic acid or methanesulfonic acid, or by treatment with a base such as sodium hydroxide or potassium hydroxide.
  • an acid such as hydrochloric acid, sulfuric acid, nitric acid, oxalic acid or methanesulfonic acid
  • a base such as sodium hydroxide or potassium hydroxide.
  • Pyrazoles of general formula II may be obtained following the procedures shown in schemes 1 and 2, below. General procedures for the preparation of pyrazoles are described in Katritzky, A. R. Handbook of Heterocyclic Chemistry, Pergamon Press, 1986.
  • R 1 9 represents halogen, methanesulfonyloxy, toluenesulfonyloxy, trifluoromethanesulfonyloxy or a group -B(OR 1 7 )(OR 1 8 ), wherein R 17 and R 18 are as described above, and L represents a leaving group.
  • a base such as an alkali metal (e.g. sodium), a metal hydride (e.g. sodium hydride) or an amidure (e.g. lithium diisopropylamidure) in a suitable solvent such as an apolar solvent, for example benzene or toluene, or an ether, for example tetrahydrofuran or diethyl ether, at a temperature between -78 °C and that of the boiling point of the solvent and during a reaction time preferably between 12 and 48 h, leads to the compounds of general formula IX.
  • a base such as an alkali metal (e.g. sodium), a metal hydride (e.g. sodium hydride) or an amidure (e.g. lithium diisopropylamidure) in a suitable solvent
  • a suitable solvent such as an apolar solvent, for example benzene or toluene, or an ether, for example tetrahydrofuran or diethyl ether
  • R 14 represents -B(OH) 2 or -Sn(R 1 6 ) 3
  • R 14 represents halogen by treatment with a suitable boronic acid ester such as triisopropylborate or with trialkyltin chloride, respectively, in the presence of a base such as butyl lithium in a polar solvent such as tetrahydrofuran.
  • a suitable boronic acid ester such as triisopropylborate or with trialkyltin chloride, respectively
  • a base such as butyl lithium in a polar solvent such as tetrahydrofuran.
  • R 1 4 represents -B(OH) 2
  • R 1 4 represents -B(OH) 2
  • compounds of formula II wherein R 14 represents -B(OR 17 )(OR 1 8 ) may be obtained from their corresponding -B(OH) 2 derivatives by treatment with a suitable alcohol such as methanol, ethanol or isopropanol, or a diol such as ethyleneglycol, propanediol or dimethylpropanediol using conventional procedures.
  • a suitable alcohol such as methanol, ethanol or isopropanol
  • a diol such as ethyleneglycol, propanediol or dimethylpropanediol
  • R 1 4 represents methanesulfonyloxy, toluenesulfonyloxy or trifluoromethanesulfonyloxy
  • R 1 4 represents methanesulfonyloxy, toluenesulfonyloxy or trifluoromethanesulfonyloxy
  • the compounds of general formula II can also be obtained by reaction of a compound of general formula X with a compound of general formula R 1 - L (XI), wherein R 1 represents C 1 -6 alkyl or -(CH 2 ) m COR 5 and L represents a leaving group such as a halogen atom, in the presence of a base such as a metal hydride (e.g. sodium hydride), an alkali metal carbona te (e.g. potassium carbonate or cesium carbonate) or a metal hydroxide (e.g.
  • a metal hydride e.g. sodium hydride
  • an alkali metal carbona te e.g. potassium carbonate or cesium carbonate
  • a metal hydroxide e.g.
  • a suitable solvent preferably a polar solvent such as a substituted amide, for example dimethylformamide, an ether, for example tetrahydrofuran or dimethoxyethane, or acetone at a temperature preferably between -20 °C and that of the boiling point of the solvent during a reaction time preferably between 2 and 24 h.
  • This reaction can also be carried out by heating a compound of formula X and the alkylating agent Ri -L in the absence of solvent at a temperature between 60 °C and that of the boiling point of the alkylating agent.
  • the compound of general formula X can be obtained by reaction of IX with hydrazine in the same experimental conditions mentioned above for the reaction of IX with V.
  • Pyrazoles of formula II wherein R 2 represents hydrogen may be prepared by a similar approach, as shown in Scheme 2.
  • the subsequent reaction of XIII with an equi valent of the a ldehyde function such as dimethylformamide dimethyl acetal leads to a compound of formula XIV.
  • Pyrazoles of formula II are then obtained from compounds of formula XIV following the same procedure described above for the preparation of II from compounds of formula IX, i.e. either reaction with a hydrazine derivative of formula V or reaction with hydrazine and subsequent alkylation of the resulting pyrazole with a compound of formula XI.
  • the compounds of general formula III wherein R 15 represents halogen are either commercially available, such as for example 2-chlorobenzonitrile, or can be prepared by methods analogous to those described in the literature starting from commercially available products.
  • the compounds of general formula III wherein R 15 represents methanesulfonyloxy, toluenesulfonyloxy or trifluoromethanesulfonyloxy are prepared from the halogenated or hydroxy compounds by procedures well known in the art.
  • the compounds of formula III can be prepared either from the corresponding halogena ted compounds following the procedures described above for compounds of formula II or by ortho-lithiation directed by suitable groups, such as 2-triphenylmethyl-2H -tetrazole, N-BOC-amino or tert- butylaminosulfonyl, and subsequent reaction with a trialkylborate such as triisopropylborate or trimethylborate.
  • suitable groups such as 2-triphenylmethyl-2H -tetrazole, N-BOC-amino or tert- butylaminosulfonyl, and subsequent reaction with a trialkylborate such as triisopropylborate or trimethylborate.
  • the boronic acid derivative of formula III can be obtained by reaction of 5-phenyl-2-triphenylmethyl-2H-tetrazole with triisopropylborate, as described in US patent no. 5,130,439.
  • R 4 * represents N-BOC-amino
  • the boronic acid derivative III can be obtained by reaction of N- BOC-aniline with trimethylborate as described in Guillier F. et al., J. Org. Chem . , 1995, 60, 292.
  • R 4 * represents tert-bu tylaminosu lfonyl
  • the corresponding boronic acid derivative of formula III can be obtained by treatment of N-tert-butyl benzenesulfonamide with butyl lithium and triisopropylborate.
  • R 1 5 represents -B(OR 17 ) (OR 1 8 )
  • the compounds of general formula IV can be prepared by reaction of a compound of general formula IX with a compound of general formula III, following an analogous procedure to that described above for the reaction of a compound of formula II with a compound of formula III.
  • Angiotensin II is a potent arterial vasoconstrictor, and it exerts its action by interacting with specific receptors.
  • the compounds disclosed in the present invention act as antagonists of the angiotensin II receptors.
  • the compounds of the present invention were tested in the following pharmacological tests:
  • Test 1 Angiotensin II receptor binding assays
  • the membrane fraction used in this assay was prepared from rat adrenal glands.
  • the tissues were collected in 50 mM Tris-HCl buffer, pH 7.5, so that the concentration was 20% (w/ v) and were homogenized at 1000xrpm.
  • the homogenate was centrifuged at 1000g for 10 min and the supernatant further centrifuged at 100,000g for 1 h.
  • the resulting membrane pellet was then resuspended in the above buffer at a concentration of 10 mg of protein/mL. Hundred ⁇ L aliquots of the membrane suspension were stored frozen at -70°C until used.
  • Test compounds were studied in the range of concentrations 10 -10 M - 10 -5 M. Binding was terminated by rapid filtration using a Millipore Multiscreen device. Filters were washed three times with 250 ⁇ L of the corresponding buffer containing or not 1 mM dithiothreitol. Dry filters were placed into vials containing 3 mL of scintillation fluid and the radioactivity counted in a scintillation counter. The IC 50 value (concentration for 50% displacement of the specifically bound 3 H-angiotensin II) was determined for each test compound. A similar binding assay was conducted following the methodology described above but using rat liver instead of rat adrenal glands.
  • the compounds of the present invention were found to have IC 50 values less than 50 ⁇ M.
  • Test 2 Inhibition of Angiotensin H-induced pressor response in pithed rats.
  • Test 3 Antihypertensive effects in conscious normotensive rats.
  • the compounds of the present invention are useful in the treatment of cardiovascular pathologies where the renin-angiotensin system is involved, such as primary or secondary hypertension, renal vascular hypertension, acute and chronic congestive heart failure, left ventricular hypertrophy, vascular hypertrophy, and diseases related with an elevated intraocular pressure such as glaucoma.
  • they can also be of value in the management of other pa thologies partly related to the above such as primary and secondary hyperaldosteronism, in the treatment of other disorders of renal ethiology such as diabetic nephropa thy, glomerulonephritis, scleroderma, glomerular sclerosis, renal failure, renal transplant therapy, diabetic retinopathy, and in the management of other vascular disorders such as migraine.
  • other disorders of renal ethiology such as diabetic nephropa thy, glomerulonephritis, scleroderma, glomerular sclerosis, renal failure, renal transplant therapy, diabetic retinopathy, and in the management of other vascular disorders such as migraine.
  • angiotensin II antagonists may also be useful for the treatment of cognitive disorders such as dementia, Alzheimer's disease, amnesia, and learning disorders.
  • the present invention further provides compositions that comprise a compound of the invention together with an excipient and optionally other auxiliary agents, if necessary.
  • the compounds of the present invention can be administered in different pharmaceutical preparations, the precise nature of which will depend, as it is well known, upon the chosen route of administration and the nature of the pathology to be treated.
  • compositions according to the present invention for oral administration include compressed tablets, dispersible powders, granules and capsules.
  • the active component is admixed with at least one inert diluent such as lactose, starch, mannitol, microcrystalline cellulose or calcium phosphate; granulating and disintegrating agents for example corn starch, gelatine, microcrystalline cellulose or polyvinylpyrrolidone; and lubricating agents for example magnesium stearate, stearic acid or talc.
  • the tablets may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and, thereby, provide a sustained action over a longer period.
  • Gastric film-coated or enteric film-coated tablets can be made with sugar, gelatin, hydroxypropylcellulose, or acrylic resins. Tablets with a sustained action may also be obtained using an excipient which provides regressive osmosis, such as the galacturonic acid polymers.
  • Formulations for oral use may also be presented as hard capsules of absorbable material, such as gelatin, wherein the active ingredient is mixed with an inert solid diluent and lubricating agents, or pasty materials, such as ethoxylated saturated glycerides.
  • Soft gelatin capsules are also possible, wherein the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil.
  • Dispersible powders and granules suitable for the preparation of a suspension by the addi tion of wa ter provide the active ingredient in admixture with dispersing or wetting agents, suspending agents, such as sodium carboxymethylcellu lose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, xantham gum, gum acacia, and one or more preservatives, such as methyl or n-propyl- p-hydroxybenzoate. Additional excipients, for example sweetening, flavoring and coloring agents may also be present.
  • suspending agents such as sodium carboxymethylcellu lose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, xantham gum, gum acacia
  • preservatives such as methyl or n-propyl- p-hydroxybenzoate.
  • Liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs containing commonly used inert diluents, such as distilled water, ethanol, sorbitol, glycerol, or propylene glycol. Such compositions may also comprise adjuvants such as wetting agents, suspending agents, sweetening, flavoring, perfuming, preserving agents and buffers.
  • compositions for oral administration include spray compositions, which may be prepared by known methods.
  • the sprav compositions will contain a suitable propellent.
  • Preparations for injection, according to the present invention, for parenteral administration by bolus injection or continuous infusion include sterile aqueous or non-aqueous solutions, suspensions or emulsions, in a non- toxic parentally-acceptable diluent or solvent.
  • aqueous solvents or suspending media are distilled water for injection, Ringer's solution, and isotonic sodium chloride solution.
  • non-aqueous solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, or alcohols such as ethanol.
  • These compositions may also include adjuvants such as wetting, preserving, emulsifying and dispersing agents.
  • sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use. When all of the components are sterile, the injectables will maintain the sterility if they are manufactured in sterile environment.
  • a compound of the invention may also administered in the form of suppositories for rectal administration of the drug.
  • Such compositions are prepared following conventional procedures, well known to those skilled in the art. For example, they can be prepared by mixing the active ingredient with a conventional suppository base such as cocoa butter or other glycerides.
  • the compounds of the present invention can also be administered in combination with other antihypertensives and/or diuretics and/or ACE inhibitors and /or calcium channel blockers and / or potassium channel openers.
  • the compounds of this invention can be given in combina tion wi th su ch com pou nd s a s a m i l o ri d e, a tenolol, bendroflu methi azi d e, chloro th a l idone, chlorothiazide, cloni dine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartrate, methylclothiazide, methyldopa, methyldopa hydrochloride, minoxidil, parg
  • the compounds of this invention when used for the treatment of elevated intraocular pressure, they can be administered in the form of typical pharmaceutical preparations such as the above mentioned or they can be administered in the form of topical ocular formulations, which include solutions, oinments, gels and the like.
  • the dosage and frequency of dose may vary depending upon symptoms, age and body weight of the patient, as well as upon the route of administration.
  • the compounds of the present invention may be administered for example orally to human patients in a daily dose from 0.1 to 500 mg for an adult, preferably a dosage from 2 to 150 mg, which may be administered either as a single dose or as divided doses.
  • doses outside the broader range may be required.
  • the pharmaceutical formulations for topical administration will typically contain about 0.1 % to 15% by weight of a compound of formula I.
  • This ocular preparations should contain oftalmologically-acceptable excipients.
  • tablets, capsules, syrups and injectables can be prepared following standard procedures and they are useful in the treatment of diseases related with the regulation of the renin-angiotensin system such as hypertension, congestive heart failure and elevated intraocular pressure.
  • Method B To a cooled solution (-78 °C) of 5-phenyl-2-triphenylmethyl-2-H- tetrazole (0.39 g, 1 mmol) and tetramethylethylenediamine (0.18 mL, 1.1 mmol) in anhydrous THF (4 mL) was added sec-butyllithium (1.6 M in hexanes, 0.29 mL, 1 .1 mmol) and the mixture was stirred for 20 min under an argon atmosphere. Then, trimethyl borate (0.14 mL, 1.3 mmol) was added and the mixture stirred for 1.5 h at 0 °C.
  • the title compound was obtained as a 4:1 mixture of regioisomers.
  • the regioisomers were separated by chromatography on silica gel (hexane-EtOAc mixtures of increasing polarity) to afford the title compounds (84%).
  • the potassium salt of isomer a) was prepared by treatment with KOH/EtOH and evaporation of the solvent.
  • Method B a) Ethyl 3-isopropyl-1 -propyl-5-[(2'-cyano-1 ,1'-biphenyl-4- yl)methyl]-1 H-pyrazole-4-carboxylate.

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Abstract

Les composés de formule générale (I) (ainsi que leurs sels et solvates) sont des antagonistes du récepteur de l'angiotensine II et à ce titre sont utiles dans le traitement de l'hypertension, de l'insuffisance cardiaque congestive et de l'hypertension intra-oculaire. Des compositions pharmaceutiques renfermant ces composés et des procédés pour leur préparation sont également décrits.
PCT/EP1995/003086 1994-08-02 1995-08-02 Nouveaux derives de pyrazole utilises comme antagonistes de l'angiotensine ii WO1996004273A1 (fr)

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AU32563/95A AU3256395A (en) 1994-08-02 1995-08-02 New pyrazole derivatives as angiotensin ii antagonist
US08/624,459 US5827863A (en) 1994-08-02 1995-08-02 Pyrazole derivatives as angiotensin II antagonists
JP8506213A JPH09504804A (ja) 1994-08-02 1995-08-02 アンジオテンシンｉｉ拮抗薬としての新規なピラゾール誘導体
EP95929067A EP0721454A1 (fr) 1994-08-02 1995-08-02 Nouveaux derives de pyrazole utilises comme antagonistes de l'angiotensine ii
NO961333A NO961333L (no) 1994-08-02 1996-04-01 Nye pyrazolderivater som angiotensin-II-antagonister

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ES09401711A ES2105939B1 (es) 1994-08-02 1994-08-02 Nuevos pirazoles con actividad antagonista de la angiotensina ii.

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Publication number Priority date Publication date Assignee Title
WO2008093639A1 (fr) 2007-01-29 2008-08-07 Takeda Pharmaceutical Company Limited Composé de pyrazole
CN103772282A (zh) * 2014-02-26 2014-05-07 上海毕得医药科技有限公司 一种3-叔丁基-1h-吡唑-4-甲醛的制备方法
CN103772282B (zh) * 2014-02-26 2015-09-23 上海毕得医药科技有限公司 一种3-叔丁基-1h-吡唑-4-甲醛的制备方法
US9505723B2 (en) 2014-09-01 2016-11-29 Canon Kabushiki Kaisha Compound, dispersant and toner

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NO961333D0 (no) 1996-04-01
CA2173258A1 (fr) 1996-02-15
EP0721454A1 (fr) 1996-07-17
AU3256395A (en) 1996-03-04
ES2105939B1 (es) 1998-07-01
NO961333L (no) 1996-04-01
JPH09504804A (ja) 1997-05-13
ES2105939A1 (es) 1997-10-16
US5827863A (en) 1998-10-27

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